The worldwide epidemic of obesity is associated with an increase in breast cancer risk and breast cancer- related mortality. Obese women and those with T2D are 20-60% more likely to die from breast cancer, more frequently have advanced breast cancer stage at diagnosis, and more likely to be diagnosed with estrogen receptor (ER?), progesterone receptor (PR), HER2 negative breast cancers, known as ?triple negative? breast cancer TNBC. These cancers have no specific targeted therapy and are associated with greater mortality. There are many metabolic abnormalities that occur in women with obesity, but hyperlipidemia (high cholesterol) is one of the most common metabolic abnormalities, specifically with increases very low density lipoprotein (VLDL), low density lipoprotein (LDL) and triglycerides. In epidemiology studies, this profile of hyperlipidemia is associated with breast cancer mortality. Dr. LeRoith hypothesizes that triple negative breast cancers are capable of taking up circulating cholesterol and triglycerides (TG) and utilize these lipids for growth and metastasis. Therefore, preventing the uptake and metabolism of cholesterol and TG may prevent triple negative breast cancer growth and metastasis. Little is known about how breast cancer cells regulate cholesterol uptake, and what is the fate of cholesterol after it has been taken up into the cell. Cholesterol in breast cancers may be involved in cell proliferation, by being used to generate cell membranes; it may be a signaling molecule; it may be used as a precursor to many steroid hormones; and it may also be metabolized into biologically active oxysterols (e.g. 25-hydroxycholesterol). In this proposal the LeRoith lab will determine if elevated total cholesterol, VLDL cholesterol, LDL cholesterol or triglycerides (TG) primarily promote the growth of human triple negative breast cancer in vivo using animal models of hyperlipidemia, and to determine how lowering circulating cholesterol and TG affects the growth and metastasis of human triple negative breast cancer. They will also examine how breast cancers take up cholesterol from the circulation, how they metabolize cholesterol to determine how interfering with cholesterol uptake and metabolism in the breast cancers impacts their growth. Dr. LeRoith also proposes to elucidate the interaction between breast cancer- derived 25-hydroxycholesterol and the surrounding adipose tissue macrophages influences breast cancer progression in the setting of hyperlipidemia. In these studies, mouse models with specific lipid abnormalities to model human hyperlipidemia will be used. The LeRoith lab have generated immunodeficient hyperlipidemic mouse models to specifically study the effects of hyperlipidemia on human triple negative breast cancers. This proposal will generate preclinical data to determine the role of circulating cholesterol and TGs in breast cancer progression and will uncover the importance of cholesterol and fatty acid uptake and metabolism in breast cancer progression. Dr. LeRoith's preclinical studies will lead to translation studies and that will eventually affect the poor outcomes of obese women with triple negative breast cancers.